The present invention relates to the field of antibodies, and particularly to an anti-human interleukin-17A monoclonal antibody, the preparation method and use thereof.
Interleukin 17 (IL-17) is an inflammatory cytokine secreted mainly by T helper 17 cells (Th17), and other T cells and innate immune cells such as mast cells and neutrophils can also secrete a certain amount of IL-17. It plays an important role in the pathological process of various inflammatory reactions and autoimmune diseases. The members of the IL-17 family include IL-17A, IL-17F, IL-17B, and IL-17C, IL-17 D in a homodimer form and IL-17A/F, IL-17E/IL-25 in a heterodimer form. In addition, there are two unnamed members. The IL-17 receptor (IL-17R) family includes IL-17RA, IL-17RB, IL-17RC, IL-17RD and IL-17RE, in which the homodimer IL-17A, together with the homodimer IL-17F and the heterodimer IL-17A/F, act on IL-17RA and IL-17RC. In vitro, the naive T cells are activated by stimulating with antigens and costimulatory molecules, the cytokines including transforming growth factor β (TGF-β), IL-6, IL-23 induce the differentiation of Th17, and Th17 cells secretcytokines IL-17A and IL-17F. IL-17/IL-17R complex participates in inflammatory response by activating the downstream signaling pathways such as NF-κB, c-jun N-terminal kinase (JNK) with the signal transduction complex IL-17R-Act1-TNF receptor associated factor 6 (TRAF6).
Studies have shown that IL-17 is fully involved in the pathological reactions of autoimmune diseases [Nature Reviews Drug Discovery, 2012. 11(10): 763-776]: IL-17 stimulates endothelial cells to secrete tissue factors, and promotes thrombosis; meanwhile, induces the secretion of inflammatory cytokines IL-6 and IL-8 from endothelial cells, epithelial cells, fibroblasts, macrophages and dendritic cells, and induces the occurrence of inflammatory reactions; acts on chondrocytes and then upregulates the expression of nitric oxide, resulting in cartilage destruction; meanwhile, induces osteoblasts to secrete the receptor activator of nuclear factor κ-B ligand (RANKL), promotes osteolysis and leads to bone injury.
Autoimmune diseases are caused by the tissue damage provoked by the body's autoimmune response to the autoantigen, including rheumatoid arthritis, ankylosing spondylitis, lupus erythematosus, psoriasis, and the like. Since the patients need treatment for a lifetime, and there is currently no cure for such a disease, it is known as “undead cancer”, of which the incidence in population is about 3%. Autoimmune diseases will affect the central nervous system, lung, liver, kidney and other organs, leading to degeneration or even failure of the organ functions, such that the patients are not able to work or move, and ultimately their lives are threatened. In China, about 30-40 million people suffer from autoimmune diseases, and the current treatment drugs commonly used in China cannot meet the needs of the patients. Therefore, it is very urgent to develop an effective treatment with low toxicity and side effect for these patients.
Studies in recent years have shown that inflammatory cytokines such as tumor necrosis factor (TNF)-α, IL-6, and IL-17A fully mediate the occurrence and development of autoimmune diseases, and biological preparations antagonizing the inflammatory cytokines have gradually become the main treatment of autoimmune diseases. Anti-TNF-α antibody (Humira), which is specially used in the treatment of various autoimmune diseases, has been the world's best-selling drug for two consecutive years, with sales of $12.5 billion in 2014, and anti-IL-6 receptor antibody drug ACTEMRA has also been clinically used in the treatment of rheumatoid arthritis for many years. On the other hand, still more than ⅓ patients with rheumatoid arthritis on which TNF inhibitors has the most significant treatment effect do not respond to such preparations or develop drug resistance mechanisms. Meanwhile, it is very likely that the major inflammatory cytokines of autoimmune diseases differ greatly from each other: skin tissue biopsy results from the patients with autoimmune diseases show high expression levels of cytokines IL-17, IL-6 and IL-23, IL-22 in the tissues. Meanwhile, a large number of Th17 cells are found in the patient's blood and diseased skin, which is positively correlated with the progression of the diseases [Nature Reviews Drug Discovery. 2012, 11: 763-776]. In view of the fact that the secretion of inflammatory cytokines IL-6 and chemokine CXCL1 is probably the result of activation of IL-17 signaling pathway [Nature Immunology. 2007, 8: 247-256], targeting IL-17 may be one of the strategies for the treatment of autoimmune diseases. There is evidence that drug molecules targeting the IL-17A signaling pathway can effectively prevent the progression of autoimmune diseases [The New England Journal of Medicine. 2014, 371: 326-338; Nature Review Drug Discovery. 2012, 11: 763-776].
In conclusion, the development of efficient and specific IL-17A blocking antibody for blocking IL-17A signaling pathway will provide a new choice for the treatment of autoimmune diseases. The characteristics of autoimmune diseases which are chronic and difficult to cure determine that the patients need long-teen medication. However, the complex production process of antibody drugs makes the average price of macromolecular drugs much higher than that of small molecular drugs. Therefore, the development of drugs with higher biological activity will reduce the dosage, as well as the cost of medication, and improve the availability of the drugs. Screening and obtaining anti-IL-17A antibodies with higher biological activity has been an urgent problem to be solved by the person skilled in this art.